ABSTRACT Persisting dysfunctional neuroplasticity in peripheral nerves as well as in the brain exert powerful influences on the pain experience. For example, facial trauma suffered by military personnel may heal, yet months later progress to a chronic neuropathic pain state. A facial laceration trigeminal nerve trauma model (CCI-ION) is utilized in our pursuit of mechanistic support for repurposing a noradrenergic (NA) therapeutic currently in use for treatment of post-traumatic stress disorder (PTSD) in active duty and Veteran military personnel to reduce chronic pain. The proposed studies address novel hypotheses to explore mechanistic changes that cause overactivation of NA neurons in the nucleus locus coeruleus (LC) neurons that modulate pain and their dysfunctional NA receptor signaling in two targeted brain regions. Our Preliminary Data support our overall hypothesis that neuroplastic changes in the pain network and related limbic structures modulate a shift to chronic pain. This also causes anxiety and depression related behavioral measures in our preclinical model. Our studies are unique in that we test through an extended time course compared to studies using acute injuries, to provide more clinically relevant information. We have discovered that switch from pain inhibition to facilitatio occurs through paradoxical ongoing dysregulation of NA LC neurons (Aim 1) that can be reversed pharmacologically (Aim 2). Long-term block of NA?1 receptor facilitation is proposed as therapy for chronic pain behaviors, overactivation, and maladaptive neuropathology (Aim 3). Aim 1 tests the hypothesis that chronic trigeminal neuropathic pain facilitates central sensitization by overactivation and dysregulation of LC NA neurons producing a functional shift from pain inhibition to facilitation. Maladaptive signaling mechanisms have been identified during chronic pain. Biomarker changes indicate overactivation of the LC, an important NA modulator of pain processing. Removal of LC NA influence with intracerebroventricular or trigeminal dorsal horn (spVc) microinjections of neurotoxic saporin conjugated dopamine-beta-hydroxylase antibodies specifically ablates NA neurons, reducing mechanical hypersensitivity. Aim 2 tests the hypothesis that trigeminal nerve injury shifts NA?2 receptor mediated inhibition to NA?1 receptor mediated facilitation of chronic pain assisted by GABA dysregulation. Pharmacological findings indicate that during chronic pain GABA disinhibition occurs. Thus, in chronic pain ligand-gated GABAA receptor chloride signaling becomes excitatory instead of inhibitory. Injury-induced long-term neuronal excitation causes intracellular chloride accumulation and equilibrium potential shift. Concomitant dysfunctional shift from NA?2 receptor inhibition to NA?1 receptor facilitation results in the medial prefrontal limbic cortex (mPFC) and spVc targeted by the NA LC neurons. Aim 3 tests the hypothesis that long-term treatment with prazosin will reduce the effects of dysregulated NA LC signaling. Efficacy of long-term treatment with orally dosed prazosin, a clinically used NA receptor antagonist, will be tested in the chronic facial laceration and nerve injury model. Attenuation is anticipated of hypersensitivity, anxiety, depression, and cognition related measures based on its efficacy for the treatment of Veterans with PTSD. Chronic pain induced histopathological changes, i.e. biomarker expression of cellular overactivation, cortical neuronal death and glial scar formation, are expected to be improved by long-term treatment with prazosin. The long term goal of the proposed studies is greater understanding of pain generators and neuroplastic changes precipitating dysfunctional neuronal signaling that produce chronic pain. Completion of the studies will provide scientific justification for repurposing FDA approved noradrenergic therapies that (1) have potential to decrease chronic neuropathic pain and (2) will move quickly through regulatory approvals. This would improve quality of life, return to work rates for Veterans, and decrease costs for the VA system.